Ageing and MS
Should this patient be prescribed siponimod for SPMS?
Case study
I recently saw a patient who had had MS for close to 40 years and had never been on a disease-modifying therapy. She now presents in her late 50s with progressive weakness of her right leg with an exercise-related foot drop and falls, which have been noticeable for about 4 years. She also has bladder problems with urinary frequency, urgency and urgency incontinence. MRI of the brain and spinal cord showed no new lesions in the last 10 years, and a lumbar puncture shows low spinal fluid neurofilament levels.
Questions:
Should this patient be prescribed siponimod for SPMS?
What is driving her worsening disability?
Prof G’s Opinion
Q: Should this patient be prescribed siponimod for SPMS?
No, she should not be prescribed siponimod as she doesn’t have active SPMS as defined by the NHS England’s treatment algorithm and our criteria within Barts-MS; i.e. she has had no recent relapses or focal MRI activity (new or enlarging T2 lesions), and her CSF neurofilament light chain levels are normal. Putting this lady on siponimod will expose her to all the risks of the treatment with not necessarily any benefits.
However, activity is a dynamic process, and this woman will now be monitored annually with an MRI brain and hopefully in the near future with 3 or 6 monthly plasma neurofilament levels. I have, however, put forward this patient for possible recruitment to the SIZOMUS trial (ClinicalTrials.gov Identifier: NCT03783416) in the hope that by targeting CNS resident B-cells and plasma cells, we may be able to modify the course of her disease with the expectation that we can slow down the rate of her worsening disability.
Q: What is driving her worsening disability?
I have written on this topic previously, and I would recommend you read my MS-Selfie Newsletter ‘Getting Worse’ (2-Jul-2021) and watch my YouTube talk, which explains smouldering MS in detail.
I suspect the main driver of worsening disability in this lady is ageing. As you are all aware, ageing is a fact of life. Even bacteria and fungi age. Ageing is, therefore, a biological process and is driven by various biological pathways and networks controlled by our genes. The senescence programmes built into our genomes are essential for evolution to function efficiently. It is well known that chronic inflammation results in accelerated ageing, and there is a hypothesis that multiple sclerosis (MS) causes premature ageing and is one of the drivers of smouldering or non-relapsing progressive MS.
From the age of about 35, the functioning of our nervous system starts to deteriorate. What protects us from this deterioration is our brain and cognitive reserve. MS reduces both and hence brings forward age-related deterioration in functioning.
One of the biological markers of ageing is the length of your chromosomes. As cells divide, the end of the chromosomes or telomeres shorten. The length of the telomeres can be used as a biological clock of ageing. The review below of seven studies in pwMS shows that pwMS have shorter telomeres than controls; in other words, they are biologically older than healthy age-matched controls.
Shorter telomeres, i.e. premature ageing, in pwMS are associated, independently of age, with greater disability, lower brain volume (end-organ damage), increased relapse rate and more rapid conversion from relapsing to progressive MS.
So is there anything you can do about the ageing process? Yes! Please make sure you are NEIDA (no evident inflammatory disease activity) and that you are doing everything you can from a health, in particular brain health, and wellness perspective, which are the only antiageing strategies at our disposal.
I am seeing an increasing number of older people with MS, i.e. 50+ years of age, who are developing progressive worsening of their functioning after many years of being NEIDA on a DMT and stable physically. When I interrogate these patients clinically, radiologically with MRI and biochemically (spinal fluid analysis), I can’t find any evidence of MS disease activity. I simply say these people have smouldering MS, but I suspect a large part of what we are seeing is age-related neurodegeneration that is occurring decades early than it should because MS has shredded their brain and cognitive reserve. The only solution to this problem is early diagnosis and treatment upfront with the aim of protecting the reserve capacity of the nervous system so that pwMS can age normally. The latter is why we launched our “MS Brain Health: Time Matters” initiative to address this problem.
Please let me know what you are doing to protect your brain and cognitive reserve? Do you feel prematurely old? What advice do you have for the next generation of pwMS?
Telomeres are protective cap structures at the end of chromosomes that are essential for maintaining genomic stability. Accelerated telomere shortening is related to premature cellular senescence. Shortened telomere lengths (TL) have been implicated in the pathogenesis of various chronic immune-mediated and neurological diseases. We aimed to systematically review the current literature on the association of TL as a measure of biological age and multiple sclerosis (MS). A comprehensive literature search was conducted to identify original studies that presented data on TL in samples from persons with MS. Quantitative and qualitative information was extracted from the articles to summarize and compare the studies. A total of 51 articles were screened, and 7 of them were included in this review. In 6 studies, average TL were analyzed in peripheral blood cells, whereas in one study, bone marrow-derived cells were used. Four of the studies reported significantly shorter leukocyte TL in at least one MS subtype in comparison to healthy controls (p=0.003 in meta-analysis). Shorter telomeres in patients with MS were found to be associated, independently of age, with greater disability, lower brain volume, increased relapse rate and more rapid conversion from relapsing to progressive MS. However, it remains unclear how telomere attrition in MS may be linked to oxidative stress, inflammation and age-related disease processes. Despite few studies in this field, there is substantial evidence on the association of TL and MS. Variability in TL appears to reflect heterogeneity in clinical presentation and course. Further investigations in large and well-characterized cohorts are warranted. More detailed studies on TL of individual chromosomes in specific cell types may help to gain new insights into the pathomechanisms of MS.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry or Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as personal clinical advice. If you have problems, please tell your own healthcare professional who will be able to help you.
Through stress of divorce and high pressure job, my MS progressed rapidly requiring a cane, orthotic foot brace, then giving up driving and using a Rollator.
After multiple false positives for JC virus while on Tysabri, I switched to fingolimod, and followed neurologist’s advice to stop working. I saw Dr Terry Wahls’ TED talk on keeping brain mitochondria healthy to avoid disability in auto-immune conditions. I researched various MS diets and advice. I heard from friends in various countries with auto-immune conditions (vitiligo, rheumatoid arthritis, psoriatic arthritis) that they were advised to avoid dairy. Given that there is limited occurrence of auto-immune conditions in countries and cultures where they eat little or no dairy products, I limited it in my own diet.
I now eat a mostly vegetarian diet, full of colourful vegetables, nuts, grass fed beef and lamb, fatty fish. I take nutrient supplements recommend for mitochondrial maintenance. I do Pilates twice per week, and walk my small dog daily. In the three years since starting this lifestyle, I have had no new brain lesions, I am able to stand longer, and walk farther. My balance has improved. The Pilates exercises I could barely do are easy now. I have found if I don’t exercise daily, my mobility suffers, I have more aches, pains, stiffness, and weakness. It is my full-time occupation to maintain my health.
I feel much better physically, but I also struggle with the fact my life is limited - socially, professionally, and financially.
If premature ageing means you can’t run a marathon or do yoga then I have always been prematurely old. I think we have unrealistic expectations of what is normal for people with and without Ms and expect eating a lot of vegetables will allow us to live a very long time. Unfortunately there are many things that will make us feel old, disappointment and grief being the most unavoidable. There is something exhausting about our quest for eternal youth and health and maybe happiness lies in not measuring ourselves continuously and finding ourselves wanting but in acceptance of our mortality, when ever that may be.